TETRAHYDROPROTOBERBERINE ANALOGS ANTAGONIZE ALPHA(1)-ADRENOCEPTORS AND INHIBIT MOBILIZATION OF INTRACELLULAR CALCIUM

Effect of tetrahydroprotoberberine (THPB) analogues 1-stepholidine (1- SPD), 1-tetrahydropalmatine (1-HTP), tetrahydroberberine (THB), and te trahydroproberberine-18 (THPB-18) on alpha(1)-adrenoceptors and cellul ar Ca2+ dynamics were studied by radioligand binding assay and vascula r contractile functional determination. In membrane preparations of ra t cerebral cortex 1-SPD, 1-THP, THB, or THPB-18 inhibited I-125-BE 225 4 binding to alpha(1)-adrenoceptors with PKi values (-log K-i) of 5.54 +/-0.36, 5.56+/-0.47, 6.01+/-0.60, and 5.75+/-0.56, respectively. The Hill coefficients for the 4 analogs were not significantly different t o unity. The computer analysis showed that the competitive curves for the 4 analogs were fit to a one binding site model. In isolated rat ao rtae 1-SPD, 1-THP, THB, or THPB-18 inhibited phenylephrine-induced con traction with pA(2) values of 5.48+/-0.58, 5.66+/-0.54, 5.45+/-0.76, a nd 5.64+/-0.34, respectively; the slopes of the Schild plot were not s ignificantly different from unity. 1-SPD (10 mu M) and THE (10 mu M) d id not affect the CaCl2-induced contraction in calcium free Krebs solu tion containing 100 mM KCl. However, both of them noncompetitively inh ibited vasocontraction induced by intracellular Ca2+ mobilizers phenyl ephrine, 5-HT, angiotensin II, or bradykinin. These results suggest th at THPB analogs can non-subtype selectively antagonize alpha(1)-adreno ceptors and inhibit intracellular Ca2+ mobilization. (C) 1997 Wiley-Li ss, Inc.